Cigarette smoking is the leading preventable cause of cancer mortality and accounts for more than 30% of all cancer deaths in the United States. Despite warnings about its adverse health effects, the prevalence of smoking is still high among US persons, especially among adolescents and young adults. Most adult smokers initiated smoking before age 18 years and developed tobacco dependence during their young adulthood. Adolescent and young adult smoking remains one of the most challenging public health issues. Smoking behaviors are highly-heritable and also influenced by environments. Although genetic and other individual risk factors of smoking have been well established, only few studies examined neighborhood effects on adolescent and young adult smoking. While gene-environment interactions on smoking have been widely evaluated, the environment has been focused typically on individual- or family-level factors. No studies have investigated the interaction between adverse neighborhood conditions and genetic risk factors on smoking. In a multilevel framework, the examination of overall geographic variation in smoking behaviors, geographic heterogeneity of genetic influences on smoking, and effect modification of neighborhood disadvantages on smoking will be able to significantly facilitate improving tobacco control and the intervention in smoking cessation. Genetic alterations combined with neighborhood deprivation could prioritize the target population of the intervention through subdividing the risk levels (risk stratification) and refining prevention choices. Therefore, using the Missouri Adolescent Female Twin Study (MOAFTS) data, we will explore the hypothesis that neighborhood environments modify the influence of genetic predispositions on cigarette smoking among adolescents and young adults. Three specific aims will be addressed: (1) Quantify the small-area geographic variation in adolescent and young adult smoking; (2) Identify neighborhood characteristics that are associated with adolescent and young adult smoking; and (3) Prospectively assess if genetic influences on smoking outcomes vary across distinct neighborhood environments. We will develop neighborhood measures based on area-level data and link them to the MOAFTS data after gecoding the residential addresses of study subjects to prospectively assess the independent and interactive effects of neighborhood environment with genetic predispositions on adolescent and young adult smoking. This award will allow the applicant to gain advanced skills in research methodology and behavioral genetics of smoking behaviors. The findings from the proposed study will provide important support to further investigate gene-neighborhood interplay on smoking through the R01 mechanism. The training and research experience obtained during this award, in combination with the excellence and expertise of his mentoring team (Drs. Mario Schootman, Andrew Heath, Pamela Madden, and Graham Colditz), will promote applicant's transition to an independent academic researcher in smoking prevention and tobacco control.